New risk stratification for adjuvant nivolumab for high-risk muscle-invasive urothelial carcinoma.

Objectives: We aim to evaluate the risk of recurrence after neoadjuvant chemotherapy followed by radical cystectomy, particularly in ypT2 disease in patients with urothelial carcinoma, because it is not clear if all eligible patients with high-risk muscle-invasive urothelial carcinoma should be treated with adjuvant nivolumab. Materials and Methods: We analysed the radiological and clinicopathological features, including cT and ypT stages, of 197 patients who had undergone two to four cycles of cisplatin-based neoadjuvant chemotherapy and radical cystectomy without adjuvant chemotherapy. We stratified the risk of postoperative recurrence by these factors. Results: The median observation period was 29.6 (interquartile range, 11.4-71.7) months, and disease recurrence was observed in 58 patients. Multivariate analysis revealed that ypT stage (P = 0.019) and lymphovascular invasion (P = 0.015) were independent risk factors for postoperative recurrence. The ypT2 group (n = 38) had significantly better recurrence-free survival than the ypT3 group (n = 41) (median recurrence-free survival: not reached vs. 13.4 months, respectively, P = 0.005). In ypT2 disease, the cT2 and ypT2 group (n = 15), which was diagnosed as cT2 preoperatively and then diagnosed as ypT2 postoperatively, had significantly better recurrence-free survival than the cT3/4 and ypT2 group (n = 23) (median recurrence-free survival: not reached vs. 63.1 months, respectively, P = 0.034). There was no significant difference in recurrence-free survival between the ypT ≤ 1 (n = 106) and the cT2 and ypT2 groups (median recurrence-free survival: not reached in both, P = 0.962). Conclusion: Patients with cT2 and ypT2 stage have a relatively low risk of recurrence and thus have a lower need for adjuvant nivolumab, particularly those with ypT2.

The PGE2/Ptger4b pathway regulates ovulation by inducing intracellular actin cytoskeleton rearrangement via the Rho/Rock pathway in the granulosa cells of periovulatory follicles in the teleost medaka.

We have previously shown that the prostaglandin E2/Ptger4b receptor system is involved in ovulation in teleost medaka and induces intracellular actin cytoskeleton rearrangement in the granulosa cells of preovulatory follicles. In this study, we investigated the signaling pathways through which prostaglandin E2 induces a change in the actin cytoskeleton. Treating preovulatory follicles with GW627368X (Ptger4b antagonist), a Rho inhibitor, or Y-27632 [Rho-associated protein kinase (Rock) inhibitor] inhibited not only in vitro follicle ovulation but also intracellular actin cytoskeleton rearrangement. Active Rhoa-c and Rock1 were detected in follicles immediately before ovulation. GW627368X also inhibited Rhoa-c activation and cytoskeleton rearrangement. PGE2-induced actin cytoskeleton rearrangement was not observed in the Ptger4b-, Rhoa-c-, or Rock1-deficient OLHNI-2 cells. These results indicate that the PGE2/Ptger4b pathway regulates intracellular actin cytoskeleton rearrangement via the Rho/Rock pathway in the granulosa cells of preovulatory follicles during medaka ovulation.

cAMP signaling in ovarian physiology in teleosts: A review.

Ovarian function in teleosts, like in other vertebrates, is regulated by two distinct gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Gonadotropin effects are mediated by membrane-bound G protein-coupled receptors localized on the surface of follicle cells. Gonadotropin receptor activation results in increased intracellular cAMP, the most important second cellular signaling molecule. FSH stimulation induces the production of 17ß-estradiol in the cells of growing follicles to promote vitellogenesis in oocytes. In contrast, in response to LH, fully grown post-vitellogenic follicles gain the ability to synthesize maturation-inducing steroids, which induce meiotic resumption and ovulation. All these events were induced downstream of cAMP. In this review, we summarize studies addressing the role of the cAMP pathway in gonadotropin-induced processes in teleost ovarian follicles. Furthermore, we discuss future problems concerning cAMP signaling in relation to teleost ovarian function and the differences and similarities in the gonadotropin-induced cAMP signaling pathways between mammals and teleosts.

Efficacy of abiraterone acetate for high-risk hormone-naïve metastatic prostate cancer: A comparison with combined androgen blockade therapy with bicalutamide and androgen deprivation therapy alone.

BACKGROUND: The treatment landscape for men with metastatic hormone-naïve prostate cancer (mHNPC) has dramatically changed with the approval of next-generation anti-androgen drugs. We compared the treatment efficacy of abiraterone with that of combined androgen blockade (CAB) therapy and androgen deprivation therapy (ADT) alone in men with high-risk mHNPC. METHODS: In total, 146 Japanese men with high-risk mHNPC were retrospectively analyzed. As initial hormonal therapy, 30, 83, and 33 men were treated with ADT plus abiraterone (ABI group), ADT plus bicalutamide (CAB group), and ADT alone (ADT group), respectively. Treatment efficacy was compared using time to castration resistance (TTCR) and prostate-specific antigen (PSA) response among the groups. Propensity score matching analysis was also performed to adjust for baseline differences. RESULTS: The median (95% confidence interval [CI]) TTCR in the ABI, CAB, and ADT groups were not reached, 10.7 (7.6-13.8) months and 11.0 (7.9-12.4) months, respectively, and it was significantly longer in the ABI group than in the other groups (p = 0.0012, p = 0.0008). In propensity score matching analysis, the median TTCR was also significantly longer in the ABI group than in the other groups (hazard ratio [HR], 0.47; 95% CI, 0.22-0.98; p = 0.010; HR, 0.32; 95% CI, 0.12-0.85; p = 0.004). The number of men who achieved PSA levels ≤0.2 ng/mL after propensity score matching were significantly higher in the ABI group than in the other groups. CONCLUSIONS: Our results provide important evidence regarding the superiority of abiraterone over CAB therapy and ADT alone for initial treatment for men with newly diagnosed mHNPC.

Stimulatory effects of collagen production induced by coenzyme Q10 in cultured skin fibroblasts.

Coenzyme Q10 (CoQ10) is a well-known antioxidant and serves as an essential carrier for electron transport and proton translocation in the mitochondrial respiratory chain. CoQ10 has been widely commercially available in Japan as a dietary and health supple-ment since 2001 and it is used for the prevention of lifestyle-related diseases induced by aging. Recently, it was stated that for Japan, which is facing an aging society, CoQ10 has been used in many skincare products. However, the physiological actions of CoQ10 in skin fibroblasts are not fully understood. In this study, we examined the effect of CoQ10 on cultured human skin fibroblast. In this study, CoQ10 treatment increased intracellular CoQ10 level and promoted proliferation of fibroblasts. In addition, CoQ10 increased mRNA expression of type I, IV, VII collagen, elastin, and HSP47, whereas CoQ10 has little effect on mRNA of type II and VIII MMP. These results suggested that CoQ10 has the efficacy that it increases collagen production in skin, thereby there is possible of the anti-aging by CoQ10 in Japan which reached an aging society, so that it might be based on new physiological function by CoQ10.

Importance of human papillomavirus vaccination leaflets focusing on the safety profile targeted pediatricians in Japan.

OBJECTIVES: To investigate the association between providing leaflets to support pediatricians in explaining the safety of the human papillomavirus (HPV) vaccine and mother's decision to vaccinate their daughters in Japan. METHODS: In this cross-sectional study, we conducted a survey of mothers to evaluate the effect of leaflets that were created to support pediatricians in explaining the safety profile of the HPV vaccine. Mothers who provided consent for vaccination before receiving an explanation were excluded from the study. The primary outcome was the mother's decision to vaccinatetheir daughters with the HPV vaccine after receiving an explanation from pediatricians using our leaflets. RESULTS: Among 161 eligible mothers, 101 decided on HPV vaccination (decided group) and 60 did not (decided against group). There was no difference in the maternal background between the 2 groups. The decided group had a significantly more positive impression of the leaflets than the undecided group. In multivariable logistic regression analysis, a detailed explanation for possible adverse events and specific solutions to them was associated with the mother's decision to have their daughters vaccinated (odds ratio 2.35, 95% confidence interval 1.02-5.44), but not the pathology of cervical cancer and the HPV vaccination process. CONCLUSION: Leaflets emphasizing an explanation of adverse events may contribute to mothers' decision making for HPV vaccination.

Development of a prognostic prediction support system for cervical intraepithelial neoplasia using artificial intelligence-based diagnosis.

OBJECTIVE: Human papillomavirus subtypes are predictive indicators of cervical intraepithelial neoplasia (CIN) progression. While colposcopy is also an essential part of cervical cancer prevention, its accuracy and reproducibility are limited because of subjective evaluation. This study aimed to develop an artificial intelligence (AI) algorithm that can accurately detect the optimal lesion associated with prognosis using colposcopic images of CIN2 patients by utilizing objective AI diagnosis. METHODS: We identified colposcopic findings associated with the prognosis of patients with CIN2. We developed a convolutional neural network that can automatically detect the rate of high-grade lesions in the uterovaginal area in 12 segments. We finally evaluated the detection accuracy of our AI algorithm compared with the scores by multiple gynecologic oncologists. RESULTS: High-grade lesion occupancy in the uterovaginal area detected by senior colposcopists was significantly correlated with the prognosis of patients with CIN2. The detection rate for high-grade lesions in 12 segments of the uterovaginal area by the AI system was 62.1% for recall, and the overall correct response rate was 89.7%. Moreover, the percentage of high-grade lesions detected by the AI system was significantly correlated with the rate detected by multiple gynecologic senior oncologists (r=0.61). CONCLUSION: Our novel AI algorithm can accurately determine high-grade lesions associated with prognosis on colposcopic images, and these results provide an insight into the additional utility of colposcopy for the management of patients with CIN2.

Case Study: A Japanese patient with metastatic renal cell carcinoma who achieved long-term treatment-free survival with pembrolizumab and axitinib in the KEYNOTE-426 phase III trial of pembrolizumab and axitinib versus sunitinib.

Introduction: Our patient treated with pembrolizumab and axitinib is one of the longest survivors in Japan on KEYNOTE 426, despite adverse events, including delayed-onset hepatitis. We herein present a detailed clinical course and short discussion on the case. Case presentation: This was a 49-year-old male with clear cell renal cell carcinoma and lung metastases. After cytoreductive nephrectomy, treatment with pembrolizumab plus axitinib was initiated and the patient demonstrated a radiographic partial response as best response. The main adverse event was pembrolizumab-induced delayed-onset hepatitis, which was successfully treated with prednisolone. Pembrolizumab was re-initiated and completed. Conclusion: The survival benefit in the present case may be due to the initial potent anti-cancer effects of axitinib and durable immune effects of pembrolizumab, leading to long-term treatment-free survival.

Signal pathway of LH-induced expression of nuclear progestin receptor in vertebrate ovulation.

Nuclear progestin receptor (PGR), which is induced in the follicles destined to undergo ovulation, is believed to be obligatory for rupture of the follicles during ovulation in vertebrates. Studies in some mammals and teleost medaka have revealed the outline of the central signaling pathway that leads to the PGR expression in the preovulatory follicles at ovulation. In this review, we summarize the current knowledge on what signaling mediators are involved in the LH-induced follicular expression of PGR at ovulation in these animals. LH-inducibility of follicular PGR expression is conserved. In both group of animals, activation of the LH receptor on the granulosa cell surface with LH commonly results in the increase of intracellular cAMP levels, while the downstream signaling cascades activated by high level of cAMP are totally different between mice and medaka. PGR is currently presumed to be induced via PKA/CREB-mediated transactivation and ERK1/2-dependent signaling in mice, but the receptor is induced via EPAC/RAP and AKT/CREB pathways in the teleost medaka. The differences and similarities in the signaling pathways for PGR expression between them is discussed from comparative and evolutionary aspects. We also discussed questions concerning PGR expression and its regulation needed to be investigated in future.

Long-term and short-term outcomes of laparoscopic versus open resection following tube decompression for obstructive colorectal cancer: a single-center retrospective study.

PURPOSE: The benefits of laparoscopic surgery over open surgery are well documented; however, the suitability of laparoscopic surgery for obstructive colorectal cancer is still controversial. The aim of this retrospective study was to compare the clinical benefits of laparoscopic surgery vs. open surgery for obstructive colorectal cancer after tube decompression. METHODS: We analyzed the outcomes of patients who underwent laparoscopic surgery vs. open surgery for curative resection after tube decompression for obstructive colorectal cancer at our hospital between January, 2007 and March, 2018. RESULTS: This study comprised 67 patients: 29 patients who underwent open surgery and 38 patients who underwent laparoscopic surgery. The morbidity within 30 days after surgery was comparable between the groups. The 3-year overall survival rates of the open and laparoscopic groups were 83.3 and 79.4%, respectively (p = 0.6244), and the 3-year disease-free survival rates were 59.3 and 71.2%, respectively (p = 0.3200). Multivariate analysis showed that nodal stage (p = 0.021) was an independent prognostic factor for OS and sex (p = 0.010) and side-ness (p = 0.048) were independent prognostic factors for DFS. CONCLUSION: If adequate decompression is achieved, laparoscopic resection following tube decompression for obstructive colorectal cancer can be a safe alternative to open surgery.

Protective effects of coenzyme Q10 on cell damage induced by hydrogen peroxides in cultured skin fibroblasts.

Cellular senescence is an intricate and multifactorial phenomenon, which is characterized by an irreversible cellular growth arrest, it is caused in response to irretrievably DNA damage, telomere shorting, activation of oncogene, and oxidative stress. Human diploid fibroblasts are a well-established experimental model for premature senescence-related studies, and exposure of fibroblasts to H2O2 is widely used as a SIPS model. Recently, it has been reported many studies of CoQ10 as to anti-aging effects, however the effect of CoQ10 on H2O2-induced SIPS model of human skin fibroblasts has not been understood. So that, we investigated that human skin fibroblasts were used to investigate the prevention effect of CoQ10 against H2O2-induced SIPS model. We created SIPS model fibroblasts with treatment of 100 µM H2O2 for 2 h. In this study, CoQ10 also increased cell viability and mRNA levels of type I, IV collagen and protein level of type I collagen. Moreover, it is shown that CoQ10 suppressed oxidative stress, degradation of collagen by increasing MMP expression, and decreasing senescence-associated phenotypes (e.g. SA-ßgal positive staining and SASP) for preventing skin aging via H2O2-induced SIPS model. These results suggested that CoQ10 has possibility to be contributory for extension of healthy life expectancy in Japan.

Growth of Yellowtail (Seriola quinqueradiata) Fed on a Diet Including Partially or Completely Defatted Black Soldier Fly (Hermetia illucens) Larvae Meal.

Against a background of increased demand for fish meal (FM), black soldier fly larva is a promising alternative feed source for sustainable aquaculture. Yellowtail, the most popular farmed fish in Japan, is a carnivorous fish; therefore, it requires a high proportion of FM in its diet. This study represents the first example of yellowtail fed on a diet including insect meal as a replacement for FM. Partially defatted black soldier fly meal (PDBM) comprised 49.0% crude protein and 23.2% crude fat, while completely defatted black soldier fly meal (CDBM) contained less than 10% crude fat, as the same level as FM was achieved with defatting PDBM using hexane. In feeding trials, growth of the fish was reduced in accordance with PDBM content: 10%, 20%, and 30% in their diet. Although a diet including 8% CDBM (with the same protein composition as 10% PDBM) also resulted in decreased fish growth, growth with a diet including 16% CDBM (with the same protein composition as 20% PDBM) was significantly higher than that of 20% PDBM, and equivalent to that of 10% PDBM. Therefore, even 10% of partially or completely black soldier fly larvae meal in diets inhibited growth in juvenile yellowtail, and we found that removal of the fat fraction could improve fish growth.

High-Trough Plasma Concentration of Afatinib Is Associated with Dose Reduction.

Afatinib is used to treat non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation as a second-generation EGFR-tyrosine kinase inhibitor (TKI). Early prediction of adverse effects based on the pharmacokinetics of afatinib enables support for quality of life (QOL) in patients with no change in efficacy. We examined the pharmacokinetic relationship between trough plasma concentration and adverse effects and evaluated the utility of measuring the trough plasma concentration of afatinib as the first EGFR-TKI treatment for NSCLC in a prospective multicenter study. Twenty-four patients treated with afatinib were enrolled in this study. All blood samples were collected at the trough point, and plasma concentrations were measured using high-performance liquid chromatography-tandem mass spectrometry. Logistic regression analysis for the dose reduction of afatinib was performed, and the receiver operating characteristic (ROC) curve was plotted. Although all patients started afatinib at 40 mg/day, plasma concentrations were variable, and mean and median trough plasma concentrations were 32.9 ng/mL and 32.5 ng/mL in this study, respectively. Minimum and maximum trough plasma concentrations were 10.4 ng/mL and 72.7 ng/mL, respectively. This variability was speculated to involve personal parameters such as laboratory data. However, no patient characteristics or laboratory data examined correlated with the trough plasma concentration of afatinib, except albumin. Albumin showed a weak correlation with plasma concentration (r = 0.60, p = 0.009). The trough plasma concentration of afatinib was significantly associated with the dose reduction of afatinib (p = 0.047). The area under the ROC curve (AUC) for the trough plasma concentration of afatinib was 0.81. The cut-off value was 21.4 ng/mL. The sensitivity and specificity of the cut-off as a risk factor were 0.80 and 0.75. In summary, the trough plasma concentration of afatinib was associated with continued or reduced dosage because of the onset of several adverse effects, and a threshold was seen. Adverse effects not only lower QOL but also hinder continued treatment. Measuring plasma concentrations of afatinib appears valuable to predict adverse effects and continue effective therapy.

Effects of dietary silkrose of Antheraea yamamai on gene expression profiling and disease resistance to Edwardsiella tarda in Japanese medaka (Oryzias latipes).

We previously identified a novel acidic polysaccharide, silkrose-AY, from the Japanese oak silkmoth (Antheraea yamamai), which can activate an innate immune response in mouse macrophage cells. However, innate immune responses stimulated by silkrose-AY in teleosts remain unclear. Here, we show the influence of dietary silkrose-AY in medaka (Oryzias latipes), a teleost model, in response to Edwardsiella tarda infection. Dietary silkrose-AY significantly improved the survival of fish and decreased the number of bacteria in their kidneys after the fish were artificially infected with E. tarda by immersion. We also performed a microarray analysis of the intestine, which serves as a primary barrier against microbial infection, to understand the profiles of differentially expressed genes (DEGs) evoked by silkrose-AY. The dietary silkrose-AY group showed differential expression of 2930 genes when compared with the control group prior to E. tarda infection. Gene ontology and pathway analysis of the DEGs highlighted several putative genes involved in pathogen attachment/recognition, the complement and coagulation cascade, antimicrobial peptides/enzymes, opsonization/phagocytosis, and epithelial junctional modification. Our findings thus provide fundamental information to help understand the molecular mechanism of bacterial protection offered by insect-derived immunostimulatory polysaccharides in teleosts.

A central role for cAMP/EPAC/RAP/PI3K/AKT/CREB signaling in LH-induced follicular Pgr expression at medaka ovulation†.

Nuclear progestin receptor (PGR) is a ligand-activated transcription factor that has been identified as a pivotal mediator of many processes associated with ovarian and uterine function, and aberrant control of PGR activity causes infertility and disease including cancer. The essential role of PGR in vertebrate ovulation is well recognized, but the mechanisms by which PGR is rapidly and transiently induced in preovulatory follicles after the ovulatory LH surge are not known in lower vertebrates. To address this issue, we utilized the small freshwater teleost medaka Oryzias latipes, which serves as a good model system for studying vertebrate ovulation. In the in vitro ovulation system using preovulatory follicles dissected from the fish ovaries, we found that inhibitors of EPAC (brefeldin A), RAP (GGTI298), PI3K (Wortmannin), AKT (AKT inhibitor IV), and CREB (KG-501) inhibited LH-induced follicle ovulation, while the PKA inhibitor H-89 had no effect on follicle ovulation. The inhibitors capable of inhibiting follicle ovulation also inhibited follicular expression of Pgr and matrix metalloproteinase-15 (Mmp15), the latter of which was previously shown to not only be a downstream effector of Pgr but also a proteolytic enzyme indispensable for follicle rupture in medaka ovulation. Further detailed analysis revealed for the first time that the cAMP/EPAC/RAP/PI3K/AKT/CREB signaling pathway mediates the LH signal to induce Pgr expression in preovulatory follicles. Our data also showed that phosphorylated Creb1 is a transcription factor essential for pgr expression and that Creb1 phosphorylated by Akt1, rather than PKA, may be preferably used to induce pgr expression.

Cost-effectiveness of TAS-102 plus bevacizumab versus TAS-102 monotherapy in patients with metastatic colorectal cancer.

BACKGROUND: TAS-102 plus bevacizumab is an anticipated combination regimen for patients who have metastatic colorectal cancer. However, evidence supporting its use for this indication is limited. We compared the cost-effectiveness of TAS-102 plus bevacizumab combination therapy with TAS-102 monotherapy for patients with chemorefractory metastatic colorectal cancer. METHOD: Markov decision modeling using treatment costs, disease-free survival, and overall survival was performed to examine the cost-effectiveness of TAS-102 plus bevacizumab combination therapy and TAS-102 monotherapy. The Japanese health care payer's perspective was adopted. The outcomes were modeled on the basis of published literature. The incremental cost-effectiveness ratio (ICER) between the two treatment regimens was the primary outcome. Sensitivity analysis was performed and the effect of uncertainty on the model parameters were investigated. RESULTS: TAS-102 plus bevacizumab had an ICER of $21,534 per quality-adjusted life-year (QALY) gained compared with TAS-102 monotherapy. Sensitivity analysis demonstrated that TAS-102 monotherapy was more cost-effective than TAS-102 and bevacizumab combination therapy at a willingness-to-pay of under $50,000 per QALY gained. CONCLUSIONS: TAS-102 and bevacizumab combination therapy is a cost-effective option for patients who have metastatic colorectal cancer in the Japanese health care system.

Dual fungal infection with Lomentospora prolificans and Aspergillus fumigatus: A pathogenetic diagnosis elucidated after two decades by sequential examinations.

A 44-year-old male Japanese was admitted for further post-remission treatments for acute myeloid leukemia. He developed a right orbital abscess. An isolate of Lomentospora prolificans was obtained from the lesion, and orbital biopsy also revealed the presence of Aspergillus fumigatus. This fatal case involved a concurrent dual fungal infection.

Bridge to Surgery for Obstructing Colonic Cancer: A Comparison between Right- and Left-sided Lesions.

OBJECTIVES: Few studies have compared management and outcomes of bridge to surgery (BTS) for obstructive colonic cancer according to the location of the tumor. Additional information is needed about this procedure's characteristics and short-term and long-term outcomes. We aimed to compare patient and tumor characteristics, and outcomes of BTS for obstructive right-sided versus left-sided colonic cancers. METHODS: This was a retrospective, single center, cohort study. The study cohort comprised 149 patients, including 48 with right-sided and 101 with left-sided obstructive colonic cancers, who were treated with BTS between January 2007 and December 2017. Data on medical history, investigations, treatments, and prognosis were collected from an electronic database of a single hospital. The primary end points were overall (OS) and disease-free (DFS) survival and short-term surgical outcomes. RESULTS: Significantly more patients with right-sided cancers had postoperative complications (29.2% vs. 14.9%, p = 0.039). Additionally, postoperative chemotherapy was administered to a marginally significantly greater proportion of patients with left-sided cancers (29.2% vs 45.5%, p = 0.057). The long-term outcomes were comparable between the two groups (the 5-year OS rates were 67.6% and 80.9% [p = 0.117] and the 5-year DFS rates were 62.2% and 58.6% [p = 0.671]). Multivariate analyses using all studied variables showed that lymphovascular invasion, advanced T stage, and adjuvant chemotherapy were independent poor prognostic factors. CONCLUSIONS: The long-term outcome was not different between the right- and left-sided groups. In a BTS setting, postoperative complications may reduce the compliance of adjuvant chemotherapy in right-sided cancers and affect long-term outcomes.

Roles of melatonin in the teleost ovary: A review of the current status.

Melatonin, the neurohormone mainly synthesized in and secreted from the pineal gland of vertebrates following a circadian rhythm, is an important factor regulating various physiological processes, including reproduction. Recent data indicate that melatonin is also synthesized in the ovary and that it acts directly at the level of the ovary to modulate ovarian physiology. In some teleosts, melatonin is reported to affect ovarian steroidogenesis. The direct action of melatonin on the ovary could be a possible factor promoting oocyte maturation in teleosts. A role for melatonin in follicle rupture during ovulation in the teleost medaka has recently emerged. In addition, melatonin is suggested to affect oocyte maturation by its antioxidant activity. However, the molecular mechanisms underlying these direct effects of melatonin are largely unknown.

Oncological outcomes of dose reductions in cisplatin due to renal dysfunction for patients with metastatic urothelial carcinoma.

Objective: To investigate whether dose reductions in cisplatin due to renal dysfunction were associated with worse clinical outcomes in metastatic urothelial carcinoma (UC) patients. Patients and methods: One hundred and fifty one metastatic UC patients who received first-line gemcitabine plus cisplatin (GC) salvage chemotherapy without a previous history of peri-surgical chemotherapy were included in this retrospective study. Patients with endogenous creatinine clearance of 60 mL/min or more were treated with a full dose of cisplatin, while those with 45-59 and 30-44 mL/min were treated with 75% and 50% doses, respectively. Patients were divided into three groups based on the average administered dose of cisplatin of 100% (Group A, N = 43), 99%-75% (Group B, N = 59), and less than 75% (Group C, N = 49), and therapeutic responses and the toxicity of GC were compared. Results: Complete response rates were 9.3%, 13.6%, and 14.3% in groups A, B, and C, respectively. One-year progression-free survival rates were 22.9%, 31.1%, and 36.7% in groups A, B, and C with no significant differences. One-year cancer-specific survival rates were 56.1%, 71.1%, and 68.3% in groups A, B, and C with no significant differences. A multivariate Cox's regression analysis showed that the dose of cisplatin was not an independent prognostic factor for disease progression and cancer death. Furthermore, there were no significant differences in the incidence of severe adverse events. Conclusions: Dose reductions in cisplatin due to renal dysfunction did not worsen clinical outcomes for metastatic UC.